There exist many physical conditions and diseases that cause bone loss in mammals, e.g., traumatic injures, osteoporosis, periodontal diseases, rheumatoid arthritis, and malignancies. These conditions or diseases can be treated by bone regeneration therapy. Cell growth factors are known to greatly contribute to tissue generation [for example, D. L. Stocum, Science, 276, 59 (1997)].
Although some treatments for bone regeneration now exist, methods of local-delivery of growth factors (GFs) for tissue regeneration have achieved only limited success because: (1) the half-life of GFs in the body is too short; (2) GFs become denatured, or lose their biological activity under some conditions, such as heating, sonication, exposure to organic solvents, or covalent bonding to carrier molecules [for example, M. S. Hora, et al. Pharm. Res., 7, 1190 (1990); S. Cohen, et al., Pharm. Res., 8, 713 (1991); Y. Tabata, et al. J. Controlled Release, 23, 55 (1993)]; and/or (3) it is difficult to achieve sustained delivery of GFs over an extended time period [for example, Y. Tabata, et al., Biomaterials, 19, 1781-1789 (1998); and Samuel E. Lynch, U.S. Pat. No. 7,473,678, January 2009].
Growth factors bind to the extracellular matrix (ECM), which provides a structural basis for transferring the information required for construction of complex cellular structures. The growth factors/ECM interactions involve the ionic binding of the growth factors with heparin or heparin sulfate [for example, J. Tailpale and J. Keski-Oja, FASEB J, 11, 51-59 (1997)]. Growth factors, such as platelet-derived growth factors (PDGF), transforming growth factors (TGFs), insulin-like growth factors (IGFs), fibroblastic growth factors (FGFs), epidermal growth factors (EGFs) and bone morphogenetic proteins (BMPs) are cationic at normal physiological pH because their amine groups are protonated under these conditions. Heparin and heparin sulfate are negatively charged because their carboxylic acid, sulfate and sulfamate functional groups are deprotonated at physiological pH. As a consequence, ionic binding takes place between the oppositely charged functional groups, and this property has been used to design GFs delivery systems for long circulation times in the body, and sustainable delivery of biologically active GFs. Examples include bio-degradable negatively charged gelatin hydrogel [for example, S. Cohen, et al., Pharm. Res., 8, 713 (1991); K. Yamada, et al., J. Neurosurg., 86, 871-875 (1997); Y. Tabata and Y. Ikada, Advanced Drug Delivery Reviews, 31, 287-301 (1998); and Y. Tabata, et al., Pure & Appl. Chem., 70 (6), 1277-1282 (1998)]; poly (acrylic acid) [for example, S. Cohen, et al., Pharm. Res., 8, 713 (1991); S. Chakraborty et al., Soft Matter, 2, 850-854 (2006)]; naturally occurring polymer material, alginate [for example, E. R. Edelman, et al., Biomaterials, 12, 619-626 (1991); and F. Gu, B. Amsden and R. Neufeld, J. Controlled Release, 96 (3), 463-472 (2004)]; chondroitin sulfate-chitosan sponge [e.g., Y. J. Park, et al., J. Controlled Release, 67, 385-394 (2000)]; and glycosaminoglycans [for example, W. M. Rhee and R. A. Berg, U.S. Pat. No. 5,476,666, December 1995]. These polymer materials have negatively charged carboxylate or sulfate groups. A. Rosenthal et al., U.S. Pat. No. 6,524,274, February 2003, describes the use of a hydrogel polymer to release a drug.
Thus a method to deliver various GFs sustainable for useful life at an in vivo site for bone regeneration would be of value.